Alzheimer's disease (AD) is the most common neurodegenerative disorder afflicting the elderly. AD is clinically characterized by progressive neuronal loss and inflammation, memory impairment, cognitive deficits, and behavioral changes. Neuropathologically, the AD brain is characterized by two proteinaceous aggregates, amyloid plaques, mainly composed of the amyloid β-protein (Aβ), and neurofibrillary tangles (NFT), comprised of hyperphosphorylated aggregates of the tau protein (Selkoe 2001). Two major hypotheses have driven pharmaceutical research in the search for a medication for AD: the amyloid hypothesis (Hardy and Selkoe 2002) and the cholinergic hypothesis (Bartus et al. 1982). Although significant progress has been made toward understanding the pathophysiology of AD, significant questions remain unanswered, e.g., the potential link between amyloid pathology and the cholinergic deficit observed in AD patients and the relationship between Aβ generation, neuronal cell death, and NFTs.
Aβ is derived from proteolysis of the β-amyloid precursor protein (APP), a type I integral membrane protein, following sequential cleavage by the β- and γ-secretases. The γ-secretase is a tetrameric complex that cleaves APP within its transmembrane domain, thereby liberating the intact Aβ peptide, which ranges in length from 39-43 residues (De Strooper et al. 2003). The majority of Aβ produced is 40 amino acids in length (Aβ40), whereas a small proportion (˜10%) is the 42-residue variant (Aβ42). Aβ42 is more hydrophobic, aggregates much faster than Aβ40, is more toxic than Aβ40, and is the major Aβ species found in cerebral plaques (Selkoe 2001; Iwatsubo 1994).
Despite intensive research during the last 100 years, prognosis of AD patients now is still quite the same as that of patients a century ago, since there is still no real cure available. There are two types of drugs approved by the U.S. Food and Drug Administration and used in clinic today to treat AD: Acetylcholinesterase (AchE) inhibitors and Memantine. There is ample evidence in the art that the amyloid beta peptide, the main component of the amyloid plaques that are specific to the AD etiology, has a key role in the development of AD disease (Hardy et al. 2002; Golde et al. 2006). Therefore, one of the most common strategies to lower Aβ is to diminish its production by γ- and β-secretase inhibition. One strategy was the development of gamma-secretase inhibitors; however, such inhibitors often result in serious side effects since gamma-secretase is involved in the proteolytic processing of at least 30 proteins (De Strooper et al. 2003). Yet another attractive strategy is the development of β-secretase (BACE1) inhibitors, as BACE1 knock-out mice are viable and have no obvious pathological phenotype (e.g., Roberds et al. 2001; Ohno et al. 2004; Ohno et al. 2006). Yet, there still is a continuous need for alternative approaches to lower Aβ in view of treating patients with neurodegenerative disorders, such as Alzheimer's disease.